The insulin-like growth factors (IGF-I and II) comprise a structurally homologous pair of circulating peptides of fundamental importance in mammalian growth processes. Although much evidence has accumulated supporting a role for IGF-I as a major postnatal growth factor, regulated at least in part by growth hormone, recent studies suggest a broader range of functions for this peptide, including actions on local growth processes and in cell and tissue differentiation. These observations imply that the control of IGF-I biosynthesis may be multifactorial, responding not only to hormones but also to tissue and developmentally-specific factors, and that regulation may occur at multiple levels, including gene transcription, RNA processing, and protein translation. As part of a long-term goal to define the mechanisms by which IGF-I gene expression and IGF-I biosynthesis are modulated, the focus of this application will be on the structural aspects of the IGF-I gene and its mRNAs which contribute to regulation by growth hormone, and on the molecular characterization of selected defects in the growth hormone-IGF-I axis. In this context four specific aims are proposed: 1. To define by molecular cloning and DNA sequencing all the mRNA species that result from transcription and processing of the human IGF-I gene. 2. To characterize the entire human IGF-I gene, including its promoter and regulatory regions. 3. To dissect the functions of the human IGF-I gene promoter, to identify the elements required for regulation by growth hormone, and to determine the mechanisms by which growth hormone activates IGF-I gene transcription. 4. To define by site-directed mutagenesis the structure and function of the growth hormone regulatory region of the human IGF-I gene promoter, and to determine whether mutations in this region are responsible for growth disorders.